title: Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation.
abstract: Ischemia-reperfusion (IR) injury following lung transplantation remains a major source of early morbidity and mortality. Histologically, this inflammatory process is characterized by neutrophil infiltration and activation. We previously reported that lung IR injury was significantly attenuated in plasminogen activator inhibitor-1-deficient mice. In this study, we explored the potential role of tissue plasminogen activator (tPA) in a mouse lung IR injury model. As a result, tPA knockout (KO) mice were significantly protected from lung IR injury through several mechanisms. At the cellular level, tPA KO specifically blocked neutrophil extravasation into the interstitium, and abundant homotypic neutrophil aggregation (HNA) was detected in the lung microvasculature of tPA KO mice after IR. At the molecular level, inhibition of neutrophil extravasation was associated with reduced expression of platelet endothelial cell adhesion molecule-1 mediated through the tPA/ LDL receptor-related protein/NF-κB signaling pathway, whereas increased P-selectin triggered HNA. At the functional level, tPA KO mice incurred significantly decreased vascular permeability and improved lung function following IR. Protection from lung IR injury in tPA KO mice occurs through a fibrinolysis-independent mechanism. These results suggest that tPA could serve as an important therapeutic target for the prevention and treatment of acute IR injury after lung transplantation.
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Damien J
authors.initials: DJ
authors.lastname: LaPar
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
mesh_terms: D000403:Airway Resistance; D000818:Animals; D001794:Blood Pressure; D002199:Capillary Permeability / Q000235:genetics; D008170:Lung Compliance; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects*; D019007:P-Selectin / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D015427:Reperfusion Injury / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019007:P-Selectin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D009195:Peroxidase; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9